Ionizing radiation (IR) constitutes a major part of cancer therapy and plays a critical role in cancer cures. However, IR can have adverse effects on normal tissues?both non-stochastic (normal tissue toxicity) and stochastic effects (radiation-induced carcinogenesis)?resulting from increased oxidative stress and increased DNA breakage. Particularly, acute side-effects of IR exposure are observed in rapidly renewing cell systems such as the bone marrow (BM) and gastrointestinal (GI) tract mucosa. Exposure to high doses of radiation in the abdominal or pelvic region (e.g., to treat ovarian or bladder cancers) causes acute GI injury, creating a dose-limiting factor. In addition, whole body irradiation to treat leukemia can result in acute hematopoietic injury. The acute effects of IR on normal tissues lead to dose reductions and delays in therapy that compromise the outcomes of cancer therapy. In addition, IR-induced genomic instability, which can be transmitted several cellular generations later, has been linked to subsequent carcinogenesis. With the growing number of cancer survivors, radiation-induced secondary cancer is an increasing problem as it impacts the overall quality of life and also leads to increasing health care costs. As part of this COBRE?s theme of defining the host responses to cancer therapy, knowledge of the underlying mechanisms of IR-induced injury to normal tissues is critical for developing novel pharmacological regimens to alleviate side-effects. In this context, the goal of this proposed project is to investigate the role of the transcription factor CCAAT/enhancer-binding protein delta (C/ebp delta or C/ebp?) in IR-induced normal tissue injury. Although studies by the Project Leader (PL) and other groups have implicated C/ebp? as having regulatory functions in cell cycle arrest, oxidative stress, DNA damage repair, and genomic stability, very little research has been conducted to examine the role of C/ebp? in the radiation response. Preliminary results by the PL suggest that loss of C/ebp? in mice enhances the injury processes caused or generated by IR-induced stress. We hypothesize that C/ebp? plays an important role in regulation of normal tissue response to IR and that lack of C/ebp? increases IR-induced normal tissue injury and promotes IR-induced genomic instability. We will rigorously test this hypothesis through the following Specific Aims. In Aim 1, we will determine whether lack of C/ebp? increases IR-induced normal tissue injury. In Aim 2, we will determine whether lack of C/ebp? promotes radiation-induced genomic instability. In Aim 3, we will elucidate the mechanisms by which lack of C/ebp? increases IR-induced normal tissue injury and genomic instability. The proposed experiments hold broad significance by addressing the critical gaps in our understanding of C/ebp? and its role in IR response and will lead to the identification of novel targets to treat or prevent radiation injury to normal tissues with the potential to significantly impact the efficacy of radiotherapy.